Chelating agents bind lead in soft tissues and are used in the treatment of lead poisoning to enhance urinary and
biliary excretion of lead, thus decreasing total lead levels in the body
(1). During the past 30 years, environmental
and dietary exposures to lead have decreased substantially, resulting in a considerable decrease in population blood lead
levels (BLLs) (2) and a corresponding decrease in the number of patients requiring chelation therapy. Chelating agents also
increase excretion of other heavy metals and minerals, such as zinc and, in certain cases, calcium
(1). This report describes three deaths associated with chelation-therapy--related
hypocalcemia that resulted in cardiac arrest. Several drugs are used in the
treatment of lead poisoning, including edetate disodium
calcium (CaEDTA), dimercaperol (British anti-Lewisite), D-penicillamine,
and meso-2,3-dimercaptosuccinic acid (succimer). Health-care providers who are unfamiliar with chelating agents and
are considering this treatment for lead poisoning should consult an expert in the chemotherapy of lead poisoning.
Hospital pharmacies should evaluate whether continued stocking of
Na2EDTA is necessary, given the established
risk for hypocalcemia, the availability of less toxic alternatives, and an ongoing safety review by the Food and Drug Administration (FDA).
Health-care providers and pharmacists should ensure that
Na2EDTA is not administered to children during chelation therapy.

Chelating agents, especially those intended for use in children, should be effective in reducing lead and other heavy
metals from the body without producing substantial adverse effects on levels of critical serum electrolytes, such as calcium. The
only agent recommended for intravenous (IV) chelation therapy for children is CaEDTA
(1). However, hospital formularies usually stock multiple chelation agents. One such agent,
Na2EDTA, was formerly used for treatment of hypercalcemia, but its use
has become infrequent because of concerns regarding nephrotoxicity and because of the availability of less toxic alternatives
(3). Furthermore, Na2EDTA contains a warning stating, "The use of this drug in any particular patient is recommended
only when the severity of the clinical condition justifies the aggressive measures associated with this type of
therapy."According to the package insert,
Na2EDTA is "indicated in selected patients for the emergency treatment of hypercalcemia and for
the control of ventricular arrhythmias associated with digitalis toxicity." According to FDA and CDC, the safety and
effectiveness
of Na2EDTA in pediatric patients has not been established, and its use is not recommended because it induces
hypocalcemia and possibly fatal tetany (1).

In 2005, the Texas Department of Health childhood lead poisoning surveillance program reported a death attributable
to chelation-associated hypocalcemia to CDC. Subsequently, CDC queried state and local lead-surveillance
programs regarding chelation-related fatalities; additional deaths were identified in Pennsylvania and Oregon.

Case Reports

Texas.In February 2005, a girl aged 2 years who was tested for blood lead during routine health surveillance had a
capillary BLL of 47 µg/dL. A venous BLL of 48
µg/dL obtained 12 days later confirmed the elevated BLL. A complete blood count
and iron study conducted concurrently revealed low serum iron levels and borderline anemia. On February 28, 2005, the girl
was admitted to a local medical center for combined
oral and IV chelation therapy.

The patient's blood electrolytes at admission were within normal limits. Initial medication orders included IV
Na2EDTA and oral succimer (an agent primarily used for treatment of lead poisoning). The medication order subsequently was
corrected by the pediatric resident to IV CaEDTA. At 4:00 p.m. on the day of admission, the patient received her first dose of
IV CaEDTA (300 mg in 100 mL normal saline at 25 mL/hr). At 4:35 p.m., she was administered 200 mg of oral succimer.
Her vital signs remained normal throughout the night. At 4:00 a.m. the next day, a dose of IV
Na2EDTA (instead of IV CaEDTA) was administered. An hour later, the patient's
serum calcium had decreased to 5.2 mg/dL (normal value for pediatric
patients: 8.5--10.5 mg/dL). At 7:05 a.m., the child's mother noticed that the child was limp and not breathing. Bedside procedures
did not restore a normal cardiac rhythm, and a cardiac resuscitation code was called at 7:25 a.m. The child had no palpable
pulse or audible heartbeat. Repeat laboratory values for serum drawn at 7:55 a.m. indicated that the serum calcium level was
<5.0 mg/dL despite repeated doses of calcium chloride. All attempts at resuscitation failed, and the girl was pronounced dead
at 8:12 a.m.

An autopsy revealed no results of toxicologic significance. A postmortem radiologic bone survey indicated areas of
sclerosis at the metaphyses (growth arrest and recovery lines compatible with lead exposure). The cause of death was recorded as
sudden cardiac arrest resulting from hypocalcemia associated with chelation therapy. The hospital's child mortality
review board findings indicated that a dose of IV
Na2EDTA was unintentionally administered to the child.

Pennsylvania. In August 2005, a boy aged 5 years with autism died while receiving IV chelation therapy with
Na2EDTA in a physician's office.During the chelation procedure, the mother noted that the child was limp. The physician
initiated resuscitation, and an emergency services team transported the child to the hospital. At the emergency
department (ED), further resuscitation was attempted, including administration of at least 1 and possibly 2 doses of IV calcium
chloride. Subsequently, the boy's blood calcium level was recorded in the ED as 6.9 mg/dL. The child did not
regain consciousness. The coroner examination indicated cause of death as diffuse, acute cerebral hypoxic-ischemic injury, secondary to
diffuse subendocardial necrosis. The myocardial necrosis resulted from
hypocalcemia associated with administration of
Na2EDTA. The case is under investigation by the Pennsylvania State Board of Medicine.

Oregon. In August 2003, a woman aged 53 years with no evidence of coronary artery disease, intracranial disease, or
injury was treated with 700 mg IV EDTA in a naturopathic practitioner's clinic. The EDTA was provided by a
compounding laboratory (Creative Compounding, Wilsonville, Oregon) and was administered by the practitioner to remove heavy
metals from the body. The practitioner had provided a similar treatment to the patient on three previous occasions, once in
June 2003 and twice in July 2003. Approximately 10--15 minutes after treatment began, the patient became
unconscious. Cardiopulmonary resuscitation was initiated, and an emergency services team was contacted. Attempts to revive the
patient en route to and in the ED were unsuccessful. The medical examiner determined the cause of death to be cardiac
arrhythmia resulting from hypocalcemia associated with EDTA infusion and vascuolar cardiomyopathy. The patient's ionized
calcium level during code was 3.8 mg/dL (normal value for adult
patients: 4.5--5.3 mg/dL) after one IV injection of
calcium gluconate administered by emergency medical
technicians en route to the hospital and another IV injection of calcium chloride in
the ED. The Oregon State Naturopath Licensing Board is conducting an investigation to determine whether
Na2EDTA or CaEDTA was administered to this patient.

The cases described in this report have been reported to FDA. FDA is performing a safety assessment of
Na2EDTA, including a review of the adverse event reporting system to determine whether other deaths related to use of chelating
agents have been reported.

Editorial Note:

Both children and adults are subject to
potentially lethal prescription errors involving "look-alike,
sound-alike" substitutions (i.e., confusion of drugs with similar names). In a 1-year study of errors in a tertiary care teaching
hospital, 11.4% of medication errors were found to have resulted from use of the wrong drug name, dosage form, or abbreviation
(4). A review of medical records in the Texas case described in this report revealed that the brand names for the
Na2EDTA product,
Endrate® (Hospira, Inc., Lake Forest, Illinois), and the CaEDTA product, Calcium Disodium
Versenate® (3M Pharmaceuticals, St. Paul, Minnesota), were used interchangeably; this improper use of drug names likely resulted in
the inappropriate administration of Na2EDTA.

Although CaEDTA and succimer were ordered for one
patient and the formof EDTA administered to
another remains under investigation, these drugs singly or in combination probably were not responsible for the low calcium
levels.Hypercalcemia as a result of IV administration of CaEDTA has been reported
(5). Succimer by itself is a weak calcium
binder but is not associated with a drop in essential minerals such as calcium
(6). Moreover, the reported doses of CaEDTA
and succimer in the Texas case were appropriate and within established safety limits.

Medical center records and coroner reports indicate that
Na2EDTA was administered in at least two of the cases.
Na2EDTA is often part of a standard hospital formulary; however, it should never be used for treating lead or other heavy
metal poisoning in children because it induces hypocalcemia, which can lead to tetany and death
(7). The error that caused the death in Texas most likely resulted from miscommunication between the pharmacy and the pediatric unit.

Chelation therapy with CaEDTA, dimercaperol, or succimer has been the mainstay of medical management for
children with BLLs >45 µg/dL
(1). The effectiveness of chelation therapy in
improving renal or nervous system symptoms of
chronic mercury toxicity has not been established. Nonetheless, certain health-care practitioners have used chelation therapy
for autism in the belief that mercury or other heavy metals are producing the symptoms
(8). Other practitioners have recommended chelation therapy for treatment of coronary
artery disease, hoping to eliminate calcified atherosclerotic
plaques that can lead to coronary artery occlusions and myocardial infarctions. These off-label uses of chelation therapy are
not supported by accepted scientific evidence. The Institute of Medicine found no scientific evidence that chelation is an
effective therapy for autism spectrum disorder
(8). Because limited consistent data exist on the use of chelation therapy to
treat coronary artery disease, a clinical trial to
assess the safety and effectiveness of chelation therapy is being conducted by
the National Institutes of Health.*

Deaths associated with lead poisoning are rare
(9), and childhood deaths caused by cardiac arrest associated with
chelation therapy have not been documented previously
(9). As BLLs among children in the United States continue to
decline (2), fewer children require chelation therapy. Primary care providers should consult experts in the chemotherapy of lead before
using chelation drug therapy. If such an expert is not available, primary care providers should contact state or local childhood
lead poisoning prevention programs or the Lead Poisoning Prevention Branch of the National Center for Environmental
Health, CDC.

CDC and its state and local partners will continue to educate health-care providers and pharmacists to ensure
that Na2EDTA is never administered to children during chelation therapy. CDC recommends that hospital pharmacies
evaluate the need to keep Na2EDTA in their formularies. Case reports of cardiac arrest or symptoms of hypocalcemia during
chelation therapy shouldbe reported to the CDC Lead Poisoning Prevention Branch (770-488-3300) or to MedWatch, the
FDA adverse event reporting system, at http://www.fda.gov/medwatch.

Acknowledgments

This report is based, in part, on contributions by M Markowitz, MD, Albert Einstein College of Medicine, New York, New
York; SI Fisch, MD, Valley Baptist Hospital, Harlingen, Texas; and
E Strimlan, Allegheny County, Pennsylvania Office of the
Coroner.

References

CDC. Preventing lead poisoning in young children: a statement by the Centers for Disease Control. Atlanta, GA: CDC; 1985.

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